A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys.

A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome.

Growth performance of piglets during the first two weeks of lactation affects the development of the intestinal microbiota.

The aim of this study was to evaluate the effect of newborn piglet weight gain during the first 2 weeks of lactation on the luminal and mucosal microbiota of the ileum and colon. The microbiota from high-weight-gain (HWG) and low-weight-gain (LWG) 2-week-old piglets was characterized by amplicon length heterogeneity PCR (LH-PCR) and compared using diversity indices and multivariate statistical analyses. At birth, LWG piglets weighted in average 0.26 kg less than HWG piglets (p = .002). The weight difference between LWG and HWG piglets increased with time and reached 2.1 kg after 16 days of lactation (p < .0001). Based on these growth performance differences, estimated colostrum and milk intake was greater in HWG than in LWG piglets (p < .0001). Analysis of the LH-PCR data of the microbiota using non-metric multidimensional scaling (NMS) and blocked multiresponse permutation procedure (MRBP) revealed that the microbiota of the HWG and LWG piglets tended to differ in ileal mucosa (p = .097) and differed in colonic lumen (p = .024). The microbiota of HWG piglets had higher levels of Bacteroidetes, Bacteroides and Ruminoccocaceae, and lower proportions of Actinobacillus porcinus and Lactobacillus amylovorus when compared with those of LWG piglets. As the weight gain of nursing piglets is highly correlated with the amount of ingested colostrum and milk, the results strongly suggest that colostrum and milk intake in the first 2 weeks of life influenced the development of the gut microbiota.

Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.

THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment.

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues.

Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular cardiac dysfunction. Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2. Biopsy of skeletal muscle demonstrated disrupted immunostaining of LIMS2. This is the first report of mutations in LIMS2 and resulting disruption of the integrin linked kinase (ILK)-LIMS-parvin complex associated with LGMD.

Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study.

Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families with clinical descriptions that included childhood-onset epilepsy or seizures not part of a recognizable syndrome or an early-onset encephalopathy where standard-of-care investigations were unrevealing. Nine families met these criteria and a diagnosis was made in seven, and potentially eight, of the families. In the eight families we identified mutations in genes associated with known neurological and epilepsy disorders: ASAH1, FOLR1, GRIN2A (two families), SCN8A, SYNGAP1 and SYNJ1. A novel and rare mutation was identified in KCNQ2 and was likely responsible for the benign seizures segregating in the family though additional evidence would be required to be definitive. In retrospect, the clinical presentation of four of the patients was considered atypical, thereby broadening the phenotypic spectrum of these conditions. Given the extensive clinical and genetic heterogeneity associated with epilepsy, our findings suggest that WES may be considered when a specific gene is not immediately suspected as causal.

Bremia lactucae Infection Efficiency in Lettuce is Modulated by Temperature and Leaf Wetness Duration Under Quebec Field Conditions.

More than 80% of Canadian lettuce production is located in the province of Quebec. Yet most of our knowledge on the epidemiology of lettuce downy mildew (Bremia lactucae) is derived from controlled-condition experiments or field experiments conducted in subtropical climates and, thus, cannot readily be applied to Quebec lettuce production. The influence of temperature and leaf wetness duration on the infection efficiency (IE) of B. lactucae was studied for 4 years (2003, 2004, 2012, and 2013) under field and growth-chamber conditions. IE was defined as the ratio of the number of lesions/leaf to the airborne conidia concentration (ACC). B. lactucae ACC was measured with rotating-arm samplers three times/week. In addition, 72 lettuce trap plants/sampling day were exposed to the potential airborne B. lactucae inoculum and disease intensity was assessed after 7 days of incubation in greenhouse. Under growth-chamber conditions, an ACC of 1 conidium/m3 was sufficient to cause 1 lesion/leaf, and IE ranged from 0.25 to 1.00. Under field conditions, an ACC of 10 to 14 conidia/m3 was required to cause 1 lesion/leaf, and IE ranged from 0.02 to 0.10, except in 2004, when IE ranged from 0.03 to 1.00. IE increased with increasing leaf wetness duration but decreased with increasing temperature. Also, considering an observed average temperature range from 10 to 20°C in the area of Quebec, 2 h of leaf wetness was sufficient for infection by B. lactucae. Therefore, under Quebec lettuce production conditions, a leaf wetness period of 2 h and an ACC of 10 to 14 conidia/m3 can be used as risk indicators to facilitate disease management decisions. Also, under typical Quebec weather conditions, measuring both morning and evening leaf wetness events could be used to improve the reliability of leaf wetness duration as a downy mildew risk indicator. Further research is needed to validate these risk indicators for integration into management strategies.

Structural degree predicts functional network connectivity: a multimodal resting-state fMRI and MEG study.

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales. We investigated if consistent modality-independent functional interactions take place between brain regions, and whether these can be accounted for by underlying structural properties. We used functional MRI (fMRI) and magnetoencephalography (MEG) recordings from a population of healthy adults together with a previously described structural network. A high overlap in resting-state functional networks was found in fMRI and especially alpha band MEG recordings. This overlap was characterized by a strongly interconnected functional core network in temporo-posterior brain regions. Anatomically realistically coupled neural mass models revealed that this strongly interconnected functional network emerges near the threshold for global synchronization. Most importantly, this functional core network could be explained by a trade-off between the product of the degrees of structurally-connected regions and the Euclidean distance between them. For both fMRI and MEG, the product of the degrees of connected regions was the most important predictor for functional network connectivity. Therefore, irrespective of the modality, these results indicate that a functional core network in the human brain is especially shaped by communication between high degree nodes of the structural network.

Whole-exome sequencing expands the phenotype of Hunter syndrome.

Whole-exome sequencing (WES) has proven its utility in finding novel genes associated with rare conditions and its usefulness is being further demonstrated in expanding the phenotypes of well known diseases. We present here a family with a previously undiagnosed X-linked condition characterized by progressive restriction of joint range of motion, prominence of the supraorbital ridge, audiology issues and hernias. They had an average stature, normal occipitofrontal circumference and intelligence, absence of dysostosis multiplex and otherwise good health. A diagnosis of Hunter syndrome was determined using WES and further supported by biochemical investigations. The phenotype of this family does not correspond to either the severe or attenuated clinical subtypes of Hunter syndrome. As further atypical families are reported, this classification will need to be modified. Our findings highlight the utility of WES in expanding the recognized phenotypic spectrum of known syndromes.

Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.

Deep Learning-Generated Synthetic MR Imaging STIR Spine Images Are Superior in Image Quality and Diagnostically Equivalent to Conventional STIR: A Multicenter, Multireader Trial.

BACKGROUND AND PURPOSE: Deep learning image reconstruction allows faster MR imaging acquisitions while matching or exceeding the standard of care and can create synthetic images from existing data sets. This multicenter, multireader spine study evaluated the performance of synthetically created STIR compared with acquired STIR. MATERIALS AND METHODS: From a multicenter, multiscanner data base of 328 clinical cases, a nonreader neuroradiologist randomly selected 110 spine MR imaging studies in 93 patients (sagittal T1, T2, and STIR) and classified them into 5 categories of disease and healthy. A DICOM-based deep learning application generated a synthetically created STIR series from the sagittal T1 and T2 images. Five radiologists (3 neuroradiologists, 1 musculoskeletal radiologist, and 1 general radiologist) rated the STIR quality and classified disease pathology (study 1, n = 80). They then assessed the presence or absence of findings typically evaluated with STIR in patients with trauma (study 2, n = 30). The readers evaluated studies with either acquired STIR or synthetically created STIR in a blinded and randomized fashion with a 1-month washout period. The interchangeability of acquired STIR and synthetically created STIR was assessed using a noninferiority threshold of 10%. RESULTS: For classification, there was a decrease in interreader agreement expected by randomly introducing synthetically created STIR of 3.23%. For trauma, there was an overall increase in interreader agreement by +1.9%. The lower bound of confidence for both exceeded the noninferiority threshold, indicating interchangeability of synthetically created STIR with acquired STIR. Both the Wilcoxon signed-rank and t tests showed higher image-quality scores for synthetically created STIR over acquired STIR (P < .0001). CONCLUSIONS: Synthetically created STIR spine MR images were diagnostically interchangeable with acquired STIR, while providing significantly higher image quality, suggesting routine clinical practice potential.

Diffusion tensor imaging of white matter tract evolution over the lifespan.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.

The effect of concomitant gradient fields on diffusion tensor imaging.

Concomitant gradient fields are transverse magnetic field components that are necessarily present to satisfy Maxwell's equations when magnetic field gradients are utilized in magnetic resonance imaging. They can have deleterious effects that are more prominent at lower static fields and/or higher gradient strengths. In diffusion tensor imaging schemes that employ large gradients that are not symmetric about a refocusing radiofrequency pulse (unlike Stejskal-Tanner, which is symmetric), concomitant fields may cause phase accrual that could corrupt the diffusion measurement. Theory predicting the error from this dephasing is described and experimentally validated for both Reese twice-refocused and split gradient single spin-echo diffusion gradient schemes. Bias in apparent diffusion coefficient values was experimentally found to worsen with distance from isocenter and with increasing duration of gradient asymmetry in both a phantom and in the brain. The amount of error from concomitant gradient fields depends on many variables, including the diffusion gradient pattern, pulse sequence timing, maximum effective gradient amplitude, static magnetic field strength, voxel size, slice distance from isocenter, and partial Fourier fraction. A prospective correction scheme that can reduce concomitant gradient errors is proposed and verified for diffusion imaging.

Control of potato soft rot caused by Pectobacterium carotovorum and Pectobacterium atrosepticum by Moroccan actinobacteria isolates.

Pectobacterium carotovorum and Pectobacterium atrosepticum are dreadful causal agents of potato soft rot. Actually, there are no efficient bactericides used to protect potato against Pectobacterium spp. Biological control using actinobacteria could be an interesting approach to manage this disease. Thus, two hundred actinobacteria isolated from Moroccan habitats were tested for their ability to inhibit in vitro 4 environmental Pectobacterium strains and the two reference strains (P. carotovorum CFBP 5890 and P. atrosepticum CFBP 5889). Eight percent of these isolates were active against at least one of the tested pathogens and only 2% exhibited an antimicrobial activity against all tested Pectobacterium strains. Four bioactive isolates having the greatest pathogen inhibitory capabilities and classified as belonging to the genus Streptomyces species through 16S rDNA analysis were subsequently tested for their ability to reduce in vivo soft rot symptoms on potato slices of Bintje, Yukon Gold, Russet and Norland cultivars caused by the two pathogens P. carotovorum and P. atrosepticum. This test was carried out by using biomass inoculums and culture filtrate of the isolates as treatment. Among these, strain Streptomyces sp. OE7, reduced by 65-94% symptom severity caused by the two pathogens on potato slices. Streptomyces OE7 showed a potential for controlling soft rot on potato slices and could be useful in an integrated control program against potato soft rot pathogens in the objective to reduce treatments with chemical compounds.

Genome shuffling enhances biocontrol abilities of Streptomyces strains against two potato pathogens.

AIMS: To employ the genome shuffling technique for improving the phenotype of a biocontrol control agent of the genus Streptomyces. METHODS AND RESULTS: Two rounds of genome shuffling (GS) were carried out with Streptomyces melanosporofaciens EF-76, a geldanamycin producer. Six fusants that showed optimized in vitro antagonistic activity against Streptomyces scabies or Phytophthora infestans, two important pathogens of potato crops, were selected. All selected fusants retained the capacity to produce geldanamycin, but none overproduced this antibiotic. The higher antagonism ability appeared to result from a diversification of secreted metabolites. Seven or eight metabolites were detected in the HPLC profiles of parental strains, whereas 12-15 were detected in fusant strains. Biocontrol assays revealed that four of six fusants protected tubers more efficiently than parental strains. CONCLUSIONS: GS emerged as an elegant and rapid tool to optimize the antagonistic ability of Streptomyces strains. Optimization of the in vitro antagonistic activity against plant pathogens appears to be an effective approach to select for improved biocontrol agents. The enhanced phenotype did not depend on an overproduction of a specific antibiotic but rather on the secretion of a wider variety of secondary metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: Improved capacities of a biocontrol agent compensate for the lack of efficient chemical control of potato scab.

Future intensification of extreme Aleutian low events and their climate impacts.

Extreme Aleutian Low (AL) events have been associated with major ecosystem reorganisations and unusual weather patterns in the Pacific region, with serious socio-economic consequences. Yet, their future evolution and impacts on atmosphere-ocean interactions remain uncertain. Here, a large ensemble of historical and future runs from the Community Earth System Model is used to investigate the evolution of AL extremes. The frequency and persistence of AL extremes are quantified and their connection with climatic variables is examined. AL extremes become more frequent and persistent under the RCP8.5 scenario, associated with changes in precipitation and air temperature patterns over North America. Future changes in AL extremes also increase the variability of the sea surface temperature and net heat fluxes in the Kuroshio Extension, the most significant heat and energy flux region of the basin. The increased frequency and persistence of future AL extremes may potentially cause substantial changes in fisheries and ecosystems of the entire Pacific region as a knock-on effect.

A founder mutation in BBS2 is responsible for Bardet-Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders.

Bardet-Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472-2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.

A comprehensive transcriptomic analysis of the effect of silicon on wheat plants under control and pathogen stress conditions.

The supply of soluble silicon (Si) to plants has been associated with many benefits that remain poorly explained and often contested. In this work, the effect of Si was studied on wheat plants under both control and pathogen stress (Blumeria graminis f. sp. tritici) conditions by conducting a large transcriptomic analysis (55,000 unigenes) aimed at comparing the differential response of plants under four treatments. The response to the supply of Si on control (uninfected) plants was limited to 47 genes of diverse functions providing little evidence of regulation of a specific metabolic process. Plants reacted to inoculation with B. graminis f. sp. tritici by an upregulation of many genes linked to stress and metabolic processes and a downregulation of genes linked to photosynthesis. Supplying Si to inoculated plants largely prevented disease development, a phenotypic response that translated into a nearly perfect reversal of genes regulated by the effect of B. graminis f. sp. tritici alone. These results suggest that Si plays a limited role on a plant's transcriptome in the absence of stress, even in the case of a high-Si-accumulating monocot such as wheat. On the other hand, the benefits of Si in the form of biotic stress alleviation were remarkably aligned with a counter-response to transcriptomic changes induced by the pathogen B. graminis f. sp. tritici.

White-matter diffusion abnormalities in temporal-lobe epilepsy with and without mesial temporal sclerosis.

BACKGROUND: Although epilepsy is considered a grey-matter disorder, changes in the underlying brain connectivity have important implications in seizure generation and propagation. Abnormalities in the temporal and extratemporal white matter of patients with temporal-lobe epilepsy (TLE) and mesial temporal sclerosis (MTS) have previously been identified. Patients with TLE but without MTS often show a different course of the disorder and worse surgical outcome than patients with MTS. The purpose of this study was to determine if said white-matter abnormalities are related to the presence of MTS or if they are also present in non-lesional TLE. METHODS: Seventeen patients with TLE and MTS (TLE+uMTS), 13 patients with non-lesional TLE (nl-TLE) and 25 controls were included in the study. Diffusion tensor imaging (DTI) was used to assess tract integrity of the fornix, cingulum, external capsules and the corpus callosum. RESULTS: The white-matter abnormalities seen in the fornix appear to be exclusive to patients with MTS. Although the cingulum showed an abnormally high overall diffusivity in both TLE groups, its anisotropy was decreased only in the TLE+uMTS group in a pattern similar to the fornix. The frontal and temporal components of the corpus callosum, as well as the external capsules, demonstrated reduced anisotropy in TLE regardless of MTS. CONCLUSIONS: While some white-matter bundles are affected equally in both forms of TLE, abnormalities of the bundles directly related to the mesial temporal structures (ie, the fornix and cingulum) appear to be unique to TLE+uMTS.